Efficient and simple synthesis of substituted 3-phenyl-7-methoxybenzopyrans as pseudo-vitamin-D3 analogs

Article abstract of DOI:10.1080/00397910701545056

An efficient and simple synthesis of substituted 3-phenyl-7- methoxybenzopyrans as pseudo-vitamin-D3 analogs in good yields under mild reaction conditions is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701545056

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Efficient and Simple Synthesis of Substituted
3‐Phenyl‐7‐methoxybenzopyrans as
Pseudo‐Vitamin‐D Analogs
3
a
a
Atul Gupta & Suprabhat Ray
a
Medicinal and Process Chemistry Division , Central Drug Research
Institute , Lucknow, India
Published online: 10 Sep 2007.
To cite this article: Atul Gupta & Suprabhat Ray (2007) Efficient and Simple Synthesis of Substituted
3
‐Phenyl‐7‐methoxybenzopyrans as Pseudo‐Vitamin‐D Analogs, Synthetic Communications: An
3
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:18, 3119-3126, DOI:
0.1080/00397910701545056
1
To link to this article: http://dx.doi.org/10.1080/00397910701545056
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Synthetic Communications , 37: 3119–3126, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701545056
Efficient and Simple Synthesis of Substituted
3
-Phenyl-7-methoxybenzopyrans as Pseudo-
Vitamin-D Analogs
3
Atul Gupta and Suprabhat Ray
Medicinal and Process Chemistry Division, Central Drug Research
Institute, Lucknow, India
Abstract: An efficient and simple synthesis of substituted 3-phenyl-7-methoxybenzo-
pyrans as pseudo-vitamin-D analogs in good yields under mild reaction conditions is
described.
3
Keywords: benzopyran, estrogen receptor, Friedel-Crafts reaction, vitamin D-3
Vitamin D has a highly flexible side chain and triene sterol structure (1)
3
(Fig. 1) with 1a,25-hydroxy groups, required for efficient gene transcription,
leading to its calcemic and antiproliferative activities.
[1–5]
. The stereo-
chemistry of vitamin-D side chain also plays an important role in its biologi-
3
[6]
cal responses. Several structural modifications have been made in the side
chain of vitamin D , which include the flexible to rigid nature of the side
3
[
7,8]
chain (2–4) (Fig. 1).
the highly flexible seco-triene system of vitamin D by an aromatic ring,
Another structural modification, replacement of
3
[9,10]
led to compound 5, which showed affinity for the vitamin-D receptor.
In our efforts to search for more bone-selective, antiproliferative ligands,
which could cross react with the estrogen as well as vitamin-D receptor, we
designed and synthesized benzopyran-based pseudo-vitamin-D analogs of
3
Received in India February 8, 2007
Address correspondence to Atul Gupta, Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow 226001, India. E-mail: atisky2001@yahoo.
co.in
3
119

3
120
A. Gupta and S. Ray
Figure 1. Ligands for vitamin-D receptor.
type 6, which possess modified side chains similar to those present in vitamin
D and its synthetic analogs.
3
This communication presents an efficient and simple synthesis of substi-
tuted 3-phenyl-7-methoxybenzopyrans (6) as pseudo-vitamin-D analogs in
3
good yields, under mild reaction conditions (Scheme 1). Condensation of resor-
cinol 7 and 4-methoxy phenylacetic acid 8 in the presence of BF -OEt through
3
2
the Friedel–Crafts acylation reaction yielded 1-(2,4-dihydroxyphenyl)-2-
4-methoxyphenyl) ethanone (9) in 62% yield. Attempts to prepare
-hydroxy-3-(4-methoxyphenyl)-chroman-4-one (10) through crossed aldol
(
7
condensation of 9 with paraformaldehyde, followed by cyclization, failed.
Therefore, one of the hydroxy groups that was thought to have a critical

3-Phenyl-7-methoxybenzopyrans
3121
Scheme 1. (a) BF -OEt , heat; (b) PhCH Br, K CO , dry acetone; (c) HCHO, aq
3
2
2
2
3
NaOH; (d) Pd/C, H
2
, MeOH; (e) ethyl 4-bromobutyrate, K
CH MgI, diethyl ether.
2 3
CO , dry acetone;
(
f) CH
3
MgI, diethyl ether; (g) CH
3
2
role in reactivity (Scheme 1) was protected using benzyl bromide with
anhydrous potassium carbonate in dry acetone, giving 1-(4-benzyloxy-2-
hydroxyphenyl)-2-(4-methoxyphenyl) ethanone 11 in 72% yield. Thus, pro-
tection of the hydroxy group enabled us to get benzyl-protected chromanone
10, 7-benzyloxy-3-(4-methoxyphenyl)-chroman-4-one (12), by condensation
of 11 with paraformaldehyde in an aqueous solution of sodium hydroxide in

3
122
A. Gupta and S. Ray
40% yield. The catalytic reduction of chromanone 12 using 10% palladium
charcoal in methanol at 50 psi pressure afforded the corresponding hydroxy
chroman 13 in 70% yield. Alkylation of 13 with ethyl-4-bromobutyrate in
the presence of anhydrous potassium carbonate in dry acetone at reflux temp-
erature furnished 4-[3-(4-methoxyphenyl)-chroman-7-yloxy] butyric acid
ethyl ester 14 in 62% yield. A Grignard reaction on compound 14 with
different alkylmagnesium halide reagents in dry THF-OEt , afforded the
2
desired compounds 15 and 16 in 94% yield. The newly synthesized
1
compounds were characterized by H NMR, IR, FAB mass spectroscopy,
and microanalysis.
EXPERIMENTAL
Anhydrous reactions were performed under an inert atmosphere; the setup was
assembled and cooled under dry nitrogen. Unless otherwise noted, starting
material, reactant, and solvents were obtained commercially and used as
such or purified and dried by standard means. The reported melting points
1
were determined in open capillaries and are uncorrected. The H NMR was
recorded on Brucker Avance DRX 200 (200 MHz, FT NMR) spectrometer
using TMS as internal standard. The chemical shifts are expressed in d
(
ppm) as values and coupling constants in Hertz. Multiplicities are
described by the following abbreviations: s for singlet, d for doublet, t for
triplet, and bs for broad singlet. Mass spectra (FAB) were recorded on a
Jeol JMS-D-300 spectrometer. The infrared spectra were recorded in KBr
on a Perkin-Elmer model 881. Elemental analyses were carried out on a
Carlo-Erba EA 1108 instrument, and results were within +0.4% of theoretical
values. The purity of the products was checked on precoated silica-gel 60
F254 thin-layer chromatography (TLC) plates, and the spots were visualized
by inspecting under short-wavelength (254-nm) UV light or by the colors
developed with iodine vapors. The column chromatography was performed
on silica gel.
Synthesis of 1-(2,4-Dihydroxyphenyl)-2-(4-methoxyphenyl)-
ethanone (9)
A mixture of resorcinol 7 (16.5 g, 0.15 mol) and p-methoxy phenylacetic acid
8
(24.3 g, 0.15 mol) dissolved in a boron–diethyl ether complex (BF –OEt )
3 2
was heated at 1008C for 6–8 h. On completion of rection, the reaction mixture
was poured onto ice-cold water and extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulphate and concentrated. The crude
material on chromatography yielded pure compound 9.
2
1
Yield: 62%, mp 156–1588C. FABMS: 258; IR (cm ): 3359, 2836, 1614,
1
511, 1353, 1179, 852, 792, 616. H NMR (d): 3.76 (s, 3H, OCH ), 4.12
1
3

3-Phenyl-7-methoxybenzopyrans
3123
(
s, 2H, CH ), 6.50 (m, 2H, ArH), 6.86 (d, J ¼ 8.54 Hz, 2H, ArH), 7.20
2
(
d, J ¼ 7.90 Hz, 2H, ArH), 7.74 (d, J ¼ 6.50 Hz, 1H, ArH). Anal. calcd. for
C H O : C, 69.76; H, 5.43. Found: C, 69.82; H, 5.71.
15 14 4
Synthesis of 1-(4-Benzyloxy,2-hydroxyphenyl)-2-
4-methoxyphenyl)-ethanone (11)
(
A mixture of 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)-ethanone 9
2.58 g, 0.01 mol), benzyl bromide (2.56 g, 0.015 mol), and anhydrous
K CO in dry acetone (50 ml) was heated under reflux for 24 h. The
(
2
3
reaction mixture was filtered and concentrated. The crude oil was taken in
ethyl acetate, washed with water, dried over anhydrous sodium sulphate,
and chromatographed through silica gel using ethyl acetate–hexane as
eluent. The pure fractions were collected and concentrated to give the
desired compound 11.
2
1
Yield: 72%, mp 90–928C. FABMS: 349; IR (cm ): 3428, 2963, 1610,
1
594, 1240, 797; H NMR (d): 3.76 (s, 3H, OCH ), 4.12 (s, 2H, CH ), 5.05
1
3
2
(
(
s, 2H, CH ), 6.50 (m, 2H, ArH), 6.86 (d, J ¼ 8.54 Hz, 2H, ArH), 7.20
2
d, J ¼ 7.90 Hz, 2H, ArH), 7.36 (m, 5H, ArH), 7.74 (d, J ¼ 6.50 Hz, 1H,
ArH). Anal. calcd. for C H O : C, 75.86; H, 5.74. Found: C, 76.01; H, 5.82.
22 20 4
Synthesis of 7-Benzyloxy-3-(4-methoxyphenyl)-chroman-4-one (12)
Compound 11 (2.0 g, 0.006 mol) dissolved in 30 ml of 30% aqueous NaOH
solution diluted with 120 ml of distilled water was heated at 608C with
stirring. To this mixture, a solution of paraformaldehyde (0.30 g, 0.01 mol)
dissolved in 2 ml of 30% aqueous NaOH solution diluted with 4 ml of
distilled water was added. The reaction mixture was further stirred for 2 h.
On cooling, the solid material was filtered and purified by column chromato-
graphy on silica gel using ethyl acetate–hexane as eluent to yield pure
compound 12.
2
1
Yield: 48%, mp 122–1248C. FABMS: 361; IR (cm ): 1683, 1609,
1
245, 831, 693; H NMR (d): 3.78 (s, 3H OCH ), 4.14 (bs, 2H, CH ), 5.01
1
3
2
(
s, 2H, CH ), 6.50 (m, 3H, CH & ArH), 6.87 (d, J ¼ 8.54 Hz, 2H, ArH),
2
7
.17 (d, J ¼ 8.36 Hz, 2H, ArH), 7.37 (m, 5H, ArH), 7.75 (d, J ¼ 9.62 Hz,
1
H, 5.83.
H, ArH). Anal. calcd. for C H O : C, 76.66; H, 5.55. Found: C, 76.74;
2
3 20 4
Synthesis of 3-(4-Methoxyphenyl)-chroman-7-ol (13)
A mixture of chromanone 12 (0.50 g, 0.0014 mol) in methanol and 10%
palladium charcoal (0.05 g) was hydrogenated at 40–50 psi pressure for

3
124
A. Gupta and S. Ray
6–8 h. The catalyst was filtered off, and solvent was evaporated to dryness.
The crude product was purified by column chromatography on silica gel
using 5% ethyl acetate–hexane as eluent to yield pure compound 13.
2
1
Yield: 70%, mp 148–1508C. FABMS: 256; IR (cm ): 3428, 2967, 2930,
1
607, 1241, 1153, 804; H NMR (d): 2.91 (dd, 2H, CH ), 3.80 (s, 3H, OCH ),
1
3
6
2
3
.15 (m, 1H, CH), 3.95 (dd, 1H, CH), 4.25 (dd, 1H, CH), 6.38 (m, 2H, ArH),
.89 (d, J ¼ 8.09 Hz, 3H, ArH), 7.18 (d, J ¼ 8.16 Hz, 2H, ArH). Anal. calcd.
for C H O : C, 75.00; H, 6.25. Found: C, 75.37; H, 6.60.
16 16 3
Synthesis of 4-[3-(4-Methoxy-phenyl)-chroman-7-yloxy] Butyric
Acid Ethyl Ester (14)
A mixture of 3-(4-methoxyphenyl)-chroman-7-ol 13 (0.26 g, 0.001 mol),
ethyl 4-bromobutyrate (0.23 g, 0.001 mol), and anhydrous K CO in dry
2
3
acetone (100 ml) was refluxed for 24 h. The reaction mixture was filtered
and concentrated to a crude oil. The crude oil was taken in ethyl acetate,
washed with water, dried over anhydrous sodium sulphate, and chromato-
graphed on silica gel using ethyl acetate–hexane as eluent to give, pure
compound 14.
2
1
Yield: 62%, mp 86–888C. FABMS: 371; IR (cm ): 3448, 2929, 2363,
1
720, 1616, 1248, 1166, 835, 796; H NMR (d): 1.26 (t, 3H, CH ), 2.09
1
3
(
m, 2H, CH ), 2.50 (t, 2H, CH ), 2.93 (dd, 2H, CH ), 3.40 (m, 1H, CH),
2 2 2
3.94 (t, 2H, CH ), 3.99 (s, 3H, OCH ), 4.14 (q, 2H, CH ), 4.29 (dd, 2H,
2 3 2
CH ), 6.43 (m, 2H, ArH), 6.88 (d, J ¼ 8.64 Hz, 2H, ArH), 6.96
2
(
C H O : C, 71.35; H, 7.02. Found: C, 71.61; H, 7.42.
d, J ¼ 8.30 Hz, 1H, ArH), 7.16 (d, J ¼ 8.60 Hz, 2H, ArH). Anal. calcd. for
22 26 5
Synthesis of 5-[3-(4-Methoxyphenyl)-chroman-7-yloxy]-2-methyl-
pentan-2-ol (15)
In a flask, CH MgI reagent was prepared by stirring CH I (0.85 g, 0.006 mol)
3
3
with Mg metal (0.14 g, 0.006 mol) in anhydrous diethyl ether at room temp-
erature. A solution of 4-[3-(4-methoxyphenyl)-chroman-7-yloxy] butyric
acid ethyl ester (14) (0.19 g, 0.0005 mol) in anhydrous THF was added
dropwise to the reagent. The reaction mixture was allowed to stir at room
temperature for 3 h. After completion, the reaction mixture was quenched
with saturated ammonium chloride solution and extracted with ethyl
acetate. The organic layer was concentrated, and crude material was recrystal-
lized with ethyl acetate–hexane to yield pure compound 15.
2
1
Yield: 94%, mp 102–1048C. FABMS: 356; IR (cm ): 3402, 2966, 1600,
1
1
2
3
588, 1263, 831, 803; H NMR (d): 1.60 (bs, 2H, CH ), 2.09 (s, 6H, 2 Â CH ),
2
3
.03 (m, 2H, CH ), 2.27 (m, 2H, CH ), 3.07 (m, 1H, CH), 3.72 (s, 3H, OCH ),
2
2
3
.88 (m, 1H, CH), 4.07 (t, 2H, CH ), 4.22 (m, 1H, CH), 6.37 (m, 2H, ArH),
2

3-Phenyl-7-methoxybenzopyrans
3125
6
.82 (d, J ¼ 8.55 Hz, 2H, ArH), 6.89 (d, J ¼ 8.29 Hz, 1H, ArH), 7.09
(d, J ¼ 8.58 Hz, 2H, ArH). Anal. calcd. for C H O : C, 74.15; H, 7.86.
2
2 28 4
Found: C, 74.32; H, 7.39.
Synthesis of 5-[3-(4-Methoxy-phenyl)-chroman-7-yloxy]-2-ethyl-
hexan-3-ol (16)
Compound 16 was prepared using the same method described for compound
1
5, using ethyl iodide.
2
1
Yield: 94%, mp 103–1058C. FABMS: 384; IR (cm ): 3460, 2961, 1588,
1
1
2
265, 1173, 832; H NMR (d): 0.81 (m, 6H, 2 Â CH ), 1.46 (m, 4H,
3
 CH ), 1.60 (bs, 2H, CH ), 2.28 (m, 2H, CH ), 2.85 (m, 2H, CH ), 3.09
2
2
2
2
(
m, 1H, CH), 3.72 (s, 3H, OCH ), 3.86 (m, 1H, CH), 4.07 (t, 2H, CH ),
3 2
4
.22 (m, 1H, CH), 6.37 (m, 2H, ArH), 6.85 (m, 3H, ArH), 7.08
(
d, J ¼ 8.25 Hz, 2H, ArH). Anal. calcd. for C H O : C, 75.00; H, 8.33.
2
4 32 4
Found: C, 75.25; H, 8.57.
CONCLUSIONS
In conclusion, we describe an efficient and simple method for the preparation
of biologically active substituted 3-phenyl-7-methoxybenzopyrans as pseudo-
vitamin-D analogs in good yields under mild reaction conditions from inex-
3
pensive starting materials.
ACKNOWLEDGMENTS
Atul Gupta is thankful to the Council of Scientific and Industrial Research,
Government of India, India, for a senior research fellowship (SRF).
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